N-heterocyclic piperazinyl and H-heterocyclic piperazinonyl inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds of the formula A which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras: ##STR1## The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:951-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase i n vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMC-COA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin two general classes. The first are analogs of farnesyl diphosphate(FPP), while the second class of inhibitors is related to the proteinsubstrates (e.g., Ras) for the enzyme. The peptide derived inhibitorsthat have been described are generally cysteine containing moleculesthat are related to the CAAX motif that is the signal for proteinprenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al.,PNAS, 88:732-736 (1991)). Such inhibitors may inhibit proteinprenylation while serving as alternate substrates for diefarnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)). In general, deletion of the thiol from a CAAX derivativehas been shown to dramatically reduce the inhibitory potency of thecompound. However, the thiol group potentially places limitations on thetherapeutic application of FPTase inhibitors with respect topharmaco-kinetics, pharmacodynamics and toxicity. Therefore, afunctional replacement for the thiol is desirable.

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It is, therefore, an object of this invention to develop peptidomimeticcompounds that do not have a thiol moiety, and that will inhibitfarnesyl-protein transferase and thus, the post-translationalfarnesylation of proteins. It is a further object of this invention todevelop chemotherapeutic compositions containing the compounds of thisinvention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises peptidoimimetic piperazine-containingcompounds which inhibit the farnesyl-protein transferase. The instantcompounds lack a thiol moiety and thus offer unique advantages in termsof improved pharmacokinetic behavior in animals, prevention ofthiol-dependent chemical reactions, such as rapid autoxidation anddisulfide formation with endogenous thiols, and reduced systemictoxicity. Further contained in this invention are chemotherapeuticcompositions containing these farnesyl transferase inhibitors andmethods for their production.

The compounds of this invention are illustrated by the formulas A and B:##STR2##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR3##wherein: R_(1a) is selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O) m--, R¹⁰ C(O)NR ¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₁₀)₂, or R¹¹ OC(O)NR¹⁰--,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)m--, R¹⁰ C(O)NR¹⁰, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--,CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;

R² and R³ are independently selected from: H; unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, ##STR4## wherein thesubstituted group is substituted with one or more of: ##STR5## R² and R³are attached to the same C atom and are combined to form--(CH₂)_(u)--wherein one of the carbon atoms is optionally replaced by a moietyselected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ is selected from H and CH₃ ;

and any two of R², R³ and R⁴ are optionally attached to the same carbonatom; R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl,C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,heteroarylsulfonyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR6## f) --SO₂ R¹¹, or g) N(R¹⁰)2; or

R⁶ and R⁷ may be joined in a ring;

R⁷ and R^(7a) may be joined in a ring; R^(6a) is selected from: C¹⁻⁴alkyl, C³⁻⁶ cycloalkyl, heterocycle, aryl, unsubstituted or substitutedwith:

a) C¹⁻⁴ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR7## f) --SO₂ R¹¹, or g) N(R¹⁰)2;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O --, R¹¹ S(O)m--, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR ¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR ¹⁰)--, CN, NO₂, R₁₀C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR ¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR ¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

G is selected from H₂ and O;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from 0, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is selected from: a unsubstituted or substituted group selected fromaryl or heteroaryl, wherein the substituted group is substituted withone or more of the following:

a) C₁₋₄ alkyl, unsubstituted or substituted with:

C₁₋₄ alkoxy, NR⁶ R⁷, C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m)R^(6a), or --C(O)NR⁶ R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m),R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

q is 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

s is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula B: ##STR8##wherein: R^(1a) is selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰),--CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)m--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;

R² and R³ are independently selected from: H; unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, ##STR9## wherein thesubstituted group is substituted with one or more of: ##STR10## R² andR³ are attached to the same C atom and are combined to form --(CH₂)u--wherein one of the carbon atoms is optionally replaced by a moietyselected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁴ is selected from H and CH₃ ;

and any two of R², R³ and R⁴ are optionally attached to the same carbonatom;

R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,heteroarylsulfonyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR11## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ; or

R⁶ and R⁷ may be joined in a ring;

R⁷ and R^(7a) may be joined in a ring;

R^(6a) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR12## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R₁₀ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR ¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkcyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is selected from: a unsubstituted or substituted group selected fromaryl or heteroaryl, wherein the substituted group is substituted withone or more of the following:

a) C₁₋₄ alkyl, unsubstituted or substituted with: C₁₋₄ alkoxy, NR⁶ R⁷,C₃₋₆ cycloalkyl, aryl, heterocycle, HO, --S(O)_(m) R^(6a), or --C(O)NR⁶R⁷,

b) aryl or heterocycle,

c) halogen,

d) OR⁶,

e) NR⁶ R⁷,

f) CN,

g) NO₂,

h) CF₃ ;

i) --S(O)_(m) R^(6a),

j) --C(O)NR⁶ R⁷, or

k) C₃ -C₆ cycloalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

q is 1 or 2;

r is 0 to 5, provided that r is O when V is hydrogen; and

s is 1;

or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR13##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O-- and--N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from H and CH₃ ;

R² is H; ##STR14## C₁₋₅ alkyl, unbranched or branched, unsubstituted orsubstituted with one or more of:

1) aryl,

2) heterocycle,

3) OR⁶,

4) SR^(6a), SO₂ R^(6a), or ##STR15## and any two of R², R³, R⁴, and R⁵are optionally attached to the same carbon atom;

R⁶, R⁷ and R^(7a) are independently selected from:

H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl, heterocycle, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R^(6a) is selected from:

C₁₋₄ alkyl or C₃₋₆ cycloalkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ C₆ alkynyl, C_(1-C) ₆perfluoroalkyl, F, Cl, R¹⁰ --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR₁₀)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰), R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

G is selected from H₂ and O;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- orbicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- orbicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl,unsubstituted or substituted with one or two of the following:

1) C₁₋₄ alkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) aryl or heterocycle,

e) HO,

f) --S(O)_(m) R⁶, or

g) --C(O)NR⁶ R⁷,

2) aryl or heterocycle,

3) halogen,

4) OR⁶,

5) NR⁶ R⁷,

6) CN,

7) NO₂,

8) CF₃ ;

9) --S(O)_(m) R⁶,

10) --C(O)NR⁶ R⁷, or

11) C₃ -C₆ cycloalkyl;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 0 or 1;

t is 0 or 1; and

u is 4or 5;

the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula C: ##STR16##wherein: R³ and R⁴ are independently selected from H and CH₃ ;

R² is H;

or ##STR17## C₁₋₅ alkyl, unbranched or branched, unsubstituted orsubstituted with one or more of:

1) aryl,

2) heterocycle,

3) OR⁶,

4) SR^(6a), SO₂ R^(6a), or ##STR18## and R² and R³ are optionallyattached to the same carbon atom; R⁶ and R⁷ are independently selectedfrom:

H; C₁₋₄ alkyl, C₃ -C₆ cycloalkyl, aryl, heterocycle, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R^(6a) is selected from:

C₁₋₄ alkyl or C₃ -C₆ cycloalkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) halogen, or

c) aryl or heterocycle;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R ¹⁰)₂ N--C(NR ¹⁰)--, R¹⁰C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰OC(O)NR¹⁰, (R¹⁰)₂ N--C(NR ¹⁰) R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- orbicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- orbicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl,unsubstituted or substituted with one or two of the following:

1) C₁₋₄ alkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃ -C₆ cycloalkyl,

d) aryl or heterocycle,

e) HO,

f) --S(O)_(m) R⁶, or

g) --C(O)NR⁶ R⁷,

2) aryl or heterocycle,

3) halogen,

4) OR⁶,

5) NR⁶ R⁷,

6) CN,

7) NO₂,

8) CF₃ ;

9) --S(O)mR⁶,

10) --C(O)NR⁶ R⁷, or

11) C₃ -C₆ cycloalkyl;

m is 0, 1 or 2; and

or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula D:##STR19## wherein: R² R³ and R⁴ are independently selected from:hydrogen or C₁ -C₆ alkyl;

Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- orbicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- orbicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl,unsubstituted or substituted with one or two of the following:

1) C₁₋₄ alkyl, unsubstituted or substituted with:

a) C₁₋₄ alkoxy,

b) NR⁶ R⁷,

c) C₃₋₆ cycloalkyl,

d) aryl or heterocycle,

e) HO,

f) --S(O)_(m) R⁶, or

g) --C(O)NR⁶ R⁷,

2) aryl or heterocycle,

3) halogen,

4) OR⁶,

5) NR⁶ R⁷,

6) CN,

7) NO₂,

8) CF₃ ;

9) --S(O)_(m) R⁶,

10) --C(O)NR⁶ R⁷, or

11) C₃ -C₆ cycloalkyl;

m is 0, 1 or 2; and

or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

4- 1-(4-methoxybenzyl)imidazol-2-yl!-1-(2-chlorophenyl)-piperazin-2-oneand

4- 3-(4-methoxybenzyl)pyrid-4-yl!-1-(2-chlorophenyl)-piperazin-2-one

or the pharmaceutically acceptable salts or optical isomers thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. When any variable (e.g. aryl, heterocycle, R¹, R²etc.) occurs more than one time in any constituent, its definition oneach occurrence is independent at every other occurrence. Also,combinations of substituents/or variables are permissible only if suchcombinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms; "alkoxy" represents an alkyl group ofindicated number of carbon atoms attached through an oxygen bridge."Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl" is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl oracenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl,pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimlidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzox,azolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiazolyl, thienofuryl, thienothienyl, and thienyl.

As used herein in the definition of R² and R³, the term "the substitutedgroup" intended to mean a substituted C₁₋₈ alkyl, substituted C₂₋₈alkenyl, substituted C₂₋₈ alkynyl, substituted aryl or substitutedheterocycle from which the substitutent(s) R² and R³ are selected.

As used herein in the definition of R⁶, R^(6a), R⁷ and R^(7a), thesubstituted C₁₋₈ alkyl, substituted C₃ -C₆ cycloalkyl, substitutedaroyl, substituted aryl, substituted heteroaroyl, substitutedarylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycleinclude moieties containing from 1 to 3 substituents in addition to thepoint of attachment to the rest of the compound. Preferably, suchsubstitutents are selected from the group which includes but is notlimited to F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂, NO₂, CN, (C₁ -C₆alkyl)O--, --OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆ alkyl)C(O)NH--, H₂N-C(NH)-, (C₁ -C₆ alkyl)C(O)--, (C₁ -C₆ alkyl)OC(O)--, N₃, (C₁ -C₆alkyl)OC(O)NH--, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thienyl, furyl, isothiazolyl and C₁ -C₂₀ alkyl.

When R² and R³ are combined to form--(CH₂)u--, cyclic moieties areformed. Examples of such cyclic moieties include, but are not limitedto: ##STR20##

In addition, such cyclic moieties may optionally include aheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to: ##STR21##

Lines drawn into the ring systems from substituents (such as from R²,R³, R⁴ etc.) indicate that the indicated bond may be attached to any ofthe substitutable ring carbon atoms.

Preferably, R^(1a) is selected from: hydrogen, --N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰--or unsubstituted or substituted C₁ -C₆ alkyl wherein the substituenton the substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted phenyl, --N(R¹⁰)₂, R¹⁰ O--and R¹⁰ C(O)NR¹⁰ --.

Preferably, R² is selected from: H, ##STR22## and an unsubstituted orsubstituted group, the group selected from C₁₋₈ alkyl, C₂₋₈ alkenyl andC₂₋₈ alkynyl;

wherein the substituted group is substituted with one or more of:##STR23##

Preferably, R³ is selected from: hydrogen and C₁ -C₆ alkyl.

Preferably, R⁴ is hydrogen.

Preferably, R⁶, R⁷ and R^(7a) is selected from: hydrogen, unsubstitutedor substituted C₁ -C₆ alkyl, unsubstituted or substituted aryl andunsubstituted or substituted cycloalkyl. Preferably, R^(6a) isunsubstituted or substituted C₁ -C₆ alkyl, unsubstituted or substitutedaryl and unsubstituted or substituted cycloalkyl.

Preferably, R⁹ is hydrogen or methyl. Most preferably, R⁹ is hydrogen.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰ )--, --S(O)₂N(R¹⁰)--and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, Y is selected from unsubstituted or substituted phenyl,unsubstituted or substituted naphthyl, unsubstituted or substitutedpyridyl, unsubstituted or substituted furanyl and unsubstituted orsubstituted thienyl. More preferably, Y is unsubstituted or substitutedphenyl.

Preferably, Z is selected from unsubstituted or substituted phenyl,unsubstituted or substituted naphthyl, unsubstituted or substitutedpyridyl, unsubstituted or substituted furanyl and unsubstituted orsubstituted thienyl. More preferably, Z is unsubstituted phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyrrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, n and r are independently 0, 1, or 2.

Preferably s is 0.

Preferably q is 1.

Preferably, the moiety ##STR24## is selected from: ##STR25##

It is intended that the definition of any substituent or variable (e.g.,R^(1a) , R⁹, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. Thus, --N(R¹⁰)₂represents --NHH, --NHCH3, --NHC₂ H₅, etc. It is understood thatsubstituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to providecompounds that are chemically stable and that can be readily synthesizedby techniques known in the art, as well as those methods set forthbelow, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-22, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R, R^(a) andR^(b) , as shown in the Schemes, represent the substituents R², R³, R⁴,and R⁵ ; however their point of attachment to the ring is illustrativeonly and is not meant to be limiting.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes.

Synopsis of Schemes 1-16:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.In Scheme 1, for example, the synthesis of suitably substitutedpiperazines is outlined, and is essentially that described by J. S.Kiely and S. R. Priebe in Organic Preparations and Proceedings Int.,1990, 22, 761-768. Boc-protected amino acids I, available commerciallyor by procedures known to those skilled in the art, can be coupled toN-aryl amino acid esters using a variety of dehydrating agents such asDCC (dicyclohexycarbodiimide) or EDC.HCL(1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride) in asolvent such as methylene chloride, chloroform, dichloroethane, or indimethylformamide. The product II is then deprotected with acid, forexample hydrogen chloride in chloroform or ethyl acetate, ortrifluoroacetic acid in methylene chloride, and cyclized under weaklybasic conditions to give the diketopiperazine III. Reduction of III withlithium aluminum hydride in refluxing ether gives the piperazine IV.

Scheme 2 illustrates the incorporation of a hetercyclic moiety on theremaining unsubstituted nitrogen of the piperazine. Thus, intermediateIV is treated with the isothiocyanate V, followed by methylationprovides the thioimidate VI. Displacement of the methyl thiol moietywith an appropriately substituted amine followed by cyclization providesthe N-imidazolyl piperazine VIII.

Scheme 2a illustrates incorporation of the preferred imidazolyl moietyon a nitrogen of a piperazinone. Thus, a suitably substituted aniline isN-alkylated sequentially with a protected acetaldehyde and a haloacetylmoiety. Reductive alkylation with an aminoimidazole, followed by basetreatment provides the 1-phenyl-4-imidazolyl-piperazin-2-one. Theimidazolyl can then be substituted with a suitably substituted benzylmoiety.

Preparation of the corresponding N-pyridyl piperazine XII is illustratedin Scheme 3. A suitably substituted benzaldehyde is coupled to4-chloropyridine to provide the pyridylphenylmethanol IX. Removal of thehydroxyl moiety followed by oxidation of the pyridinyl nitrogen provideintermediate X. Intermediate X is then reacted with the piperazine IV toprovide the instant compound XII.

Depending on the identity of the amino acid I, various side chains canbe incorporated into the piperazine. For example when I is theBoc-protected β-benzyl ester of aspartic acid, the intermediatediketopiperazine XIII where n=1 and R=benzyl is obtained, as shown inScheme 4. Subsequent lithium aluminum hydride reduction reduces theester to the alcohol XIV, which can then be reacted with a variety ofalkylating agents such as an alkyl iodide, under basic conditions, forexample, sodium hydride in dimethyliformamide or tetrahydrofuran. Theresulting ether XV can then be carried on to final products as describedin Schemes 2 and 3.

Reaction Scheme 5 provides an illustrative example the synthesis ofcompounds of the instant invention wherein the substituents R² and R³are combined to form --(CH₂)u --. For example,1-aminocyclohexane-1-carboxylic acid XVI can be converted to thespiropiperazine XVIII essentially according to the procedures outlinedin Schemes 1. The piperazine intermediate XVIII can be carried on tofinal products as described in Schemes 2-3.

Scheme 6 illustrates the use of an optionally substituted homoserinelactone XXI to prepare a Boc-protected piperazinone XXII. IntermediateXXII may be reduced, deprotected and reductively alkylated or acylatedas illustrated in the previous Schemes. Alternatively, the hydroxylmoiety of intermediate XXIII may be mesylated and displaced by asuitable nucleophile, such as the sodium salt of ethane thiol, toprovide an intermediate XXIV. Intermediate XXIII may also be oxidized toprovide the carboxylic acid on inter- mediate XXV, which can be utilizedform an ester or amide moiety.

Amino acids of the general formula XXVI which have a sidechain not foundin natural amino acids may be prepared by the reactions illustrated inScheme 18S starting with the readily prepared imine XXVII. ##STR26##

The instant compounds are useful as pharmaceutical a gents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this 5 invention include, but arenot limited to, colorectal carcinoma, exocrine pancreatic carcinoma,myeloid leukemias and neurological tumors.

Such tumors may arise by mutations in the ras genes themselves,mutations in the proteins that can regulate Ras activity (i.e.,neurofibromin (NF-1), neu, scr, ab 1 , Ick, fyn) or by other mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142: 1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal,2:A3160 (198P))).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated.

For example, the instant compounds may be useful in combination withknown anti-cancer and cytotoxic, agents. Similarly, the instantcompounds may be useful in combination with agents that are effective inthe treatment and prevention of NF- 1, restenosis, polycystic kidneydisease, infections of hepatitis delta and related viruses and fungalinfections.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range 5 described belowand the other pharmaceutically active agent(s) within its approveddosage range. Compounds of the instant invention may alternatively beused sequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine 5 terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 1 Preparation of 4- 1-(4-methoxybenzyl)imidazol-2-yl!1-(2-chlorophenyl)-piperazin-2-one.

Step A: Synthesis of 4- 5-(4-methoxyphenyl)-2-thia-4-aza-pent-3-en-3-yl!-1 -(2-chlorophenyl)-piperazin-2-one

Modifying the method of Poisson, et al., (Tetrahedron Letters 32, 5325(1991)), p-methoxybenzyl isothiocyanate (1 molar equivalent) and1-(2-chlorophenyl)-piperazine-2-one are heated in toluene at 50° C. for6 h. Without purification the product is S-methylated by treatment withmethyl iodide (3 molar equivalents) to furnish the title compound.

Step B: 4- 1-(4-methoxybenzyl)-imidazol-2-yi! - 1-(2-chlorophenyl)-piperazin-2-one.

The product of step A is treated with aminoacetaldehyde dimethyl acetal(1.5 molar equivalents) in isopropanol. The intermediate guanidine isrefluxed in isopropanol and hydrochloric acid to give the titlecompound.

Example 2

Preparation of 4- 3-(4-methoxybenzyl)pyrid-4-yl! -1-(2-chlorophenyl)-piperazin-2-one.

Step A: 4-Chloro-3-(4-methoxybenzyl)pyridine. 4-Chloropyridine istreated sequentially with LDA (1.1 molar equivalents) and4-methoxybenzaldehyde (1 molar equivalent). The resulting carbinol isisolated and deoxygenated with triethylsilane (10 molar equivalents) and50% trifluoroacetic acid in methylene chloride to provide the titlecompound.

Step B: 4-Chloro-3-(4-methoxybenzyl)pyridine-N-oxide

The product of step A is oxidized to the title compound withm-chloroperoxybenzoic acid (1.1 molar equivalents).

Step C: 4- 3-(4-methoxybenzyl)pyrid-4-yl! -1-(2-chlorophenyl)-piperazin-2-one.

The product of step B is heated with 1-(2-chlorophenyl)-piperazin-2-one(1 molar equivalent). The crude N-oxide of 4- 3-(4-methoxybenzyl)pyrid-4-yl!-I-(2-chlorophenyl)-piperazin-2-one is deoxygenated by treatmentwith triphenylphosphine (2 molar equivalents) to provide the titlecompound.

Example 3

In vitro inhibition of ras farnesyl transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-25 14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM ³ H! -farnesyl diphosphate ( ³ H! -FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0 M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach I1 cell harvestor, washed with 100%ethanol, dried and counted in an LKB βplate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the ³ H!-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for min., stopped with 100, μ of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention are tested for inhibitoryactivity against human FPTase by the assay described above.

Example 4

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRatl or NIH3T3 cells, which expressed viral Ha-ras p21.

The assay is performed essentially as described in DeClue, J. E. et al.,Cancer Research 51:712-717, (1991). Cells in cm dishes at 50-75%confluency are treated with the test compound (final concentration ofsolvent, methanol or dimethyl sulfoxide, is 0.1 %). After 4 hours at 37°C., the cells are labelled in 3 ml methionine-free DMEM supplementedwith 10% regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000 Ci/mmol). After an additional hours, the cells arelysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/1mMDTT/mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) andthe lysates cleared by centrifugation at 100,000 ×g for 45 min. Aliquotsof lysates containing equal numbers of acid-precipitable counts arebought to 1 ml with IP buffer (lysis buffer lacking DTT) andimmunoprecipitated with the ras-specific monoclonal antibody Y13-259(Furth, M. E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hourantibody incubation at 4° C., 200 ml of a 25% suspension of proteinA-Sepharose coated with rabbit anti rat IgG is added for 45 min. Theimmunoprecipitates are washed four times with IP buffer (nM HEPES, pH7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0.l %/SDS/0.I M NaCI)boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. Whenthe dye front reached the bottom, the gel is fixed, soaked inEnlightening, dried and autoradiographed. The intensities of the bandscorresponding to farnesylated and nonfarnesylated ras proteins arecompared to determine the percent inhibition of farnesyl transfer toprotein.

Example 5

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Ratl cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×104 cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 nil of medium A containing 0. I% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR27## wherein: R^(1a) is selectedfrom:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NRI¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR ¹⁰ --, c) unsubstituted or substituted C₁ -C₆ alkylwherein the substitutent on the substituted C₆ -C₆ alkyl is selectedfrom unsubstituted or substituted aryl, heterocyclic, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR10--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R² and R³ are independently selectedfrom: H; unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, ##STR28## wherein the substituted group is substituted withone or more of: ##STR29## R² and R³ are attached to the same C atom andare combined to form--(CH₂)_(u) --wherein one of the carbon atoms isoptionally replaced by a moiety selected from: O, S(O)_(m), --NC(O)--,and --N(CORI¹⁰)--; R⁴ is selected from H and CH₃ ;and any two of R², R³and R⁴ are optionally attached to the same carbon atom; ⁶. R⁷ and R^(7a)are independently selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl,heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) aryl orheterocycle, c) halogen, d) HO, ##STR30## f) --SO₂ R¹¹ or g) N(R¹⁰)₂ ;or R⁶ and R⁷ may be joined in a ring; R⁷ and R^(7a) may be joined in aring; R^(6a) is selected from: C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle,aryl, unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) aryl orheterocycle, c) halogen, d) HO, ##STR31## f) --SO₂ R¹¹, or g) N(R¹⁰)₂ ;R⁸ is independently selected from:a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --(R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R₁₀)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R₁₀ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyland aryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR₁₀ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ; G is selected from H₂and O; V is selected from:a) hydrogen, b) heterocycle, c) aryl, d) C₁-C₄ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,providedthat V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ isa bond, n is 0 and A² is S(O)_(m) ; W is a heterocycle; Z is selectedfrom: a unsubstituted or substituted group selected from aryl orheteroaryl, wherein the substituted group is substituted with one ormore of the following:a) C₁₋₄ alkyl, unsubstituted or substituted with:C₁₋₄ alkoxy, NR⁶ R⁷, C_(3-C) ₆ cycloalkyl, aryl, heterocycle, HO,--S(O)_(m) R^(6a), or --C(O)NR⁶ R⁷, b) aryl or heterocycle, c) halogen,d) OR⁶, e) NR⁶ R⁷, f) CN, g) NO₂, h) CF₃ ; i) --S(O)_(m) R^(6a), j)--C(O)NR⁶ R⁷, or k) C₃ -C₆ cycloalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3or 4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen;and s is 0; u is 4 or 5;or a pharmaceutically acceptable salt thereof.2. The compound according to claim 1 of the formula A: ##STR32##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C⁶alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl, c)unsubstituted or substituted C₆ -C₆ alkyl wherein the substitutent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O-- and--N(R¹⁰)₂ ; R³ and R⁴ are independently selected from H and CH₃ ; R² isH; ##STR33## or C₁₋₅ alkyl, unbranched or branched, unsubstituted orsubstituted with one or more of: 1) aryl, 2) heterocycle, 3) OR⁶, 4)SR^(6a), SO₂ R^(6a), or ##STR34## and any two of R², R³, R⁴, and R⁵ areoptionally attached to the same carbon atom; R⁶, R⁷ and R^(7a) areindependently selected from:H; C₁₋₄ alkyl, C_(3-C) ₆ cycloalkyl, aryl,heterocycle, unsubstituted or substituted with:a) C₁₋₄ alkoxy, b)halogen, or c) aryl or heterocycle; R^(6a) is selected from:C₁₋₄ alkylor C_(3-C) ₆ cycloalkyl, unsubstituted or substituted with:a) C₁₋₄alkoxy, b) halogen, or c) aryl or heterocycle; R⁸ is independentlyselected from:a) hydrogen, b) C₁ -C.sub.≢ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR₁₀)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R₁₁ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ (O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; G is selected from H₂ and O;V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycle selectedfrom pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is mono- orbicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclicarylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclicarylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted orsubstituted with one or two of the following:1) C₁₋₄ alkyl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c) C_(3-C)₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) --S(O)_(m) R⁶, or g)--C(O)NR⁶ R⁷, 2) aryl or heterocycle., 3) halogen, 4) OR⁶, 5) NR⁶ R⁷, 6)CN, 7) NO₂, 8) CF₃ ; 9) --S(O)_(m) R⁶, 10) --C(O)NR⁶ R⁷, or 11) C₃ -C₆cycloalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4;r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0; and u is 4or 5;or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1 of the formula C: ##STR35## wherein: R³ and R⁴ areindependently selected from H and CH₃ ;R² is H; ##STR36## or C₁₋₅ alkyl,unbranched or branched, unsubstituted or substituted with one or moreof: 1) aryl, 2) heterocycle, 3) OR⁶, 4) SR^(6a), SO₂ R^(6a), or 5)##STR37## and R² and R³ are optionally attached to the same carbon atom;R⁶ and R⁷ are independently selected from:H; C₁₋₄ alkyl, C_(3-C) ₆cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:a) C₁₋₄alkoxy, b) halogen, or c) aryl or heterocycle; R^(6a) is selectedfrom:C₁₋₄ alkyl or C_(3-C) ₆ cycloalkyl, unsubstituted or substitutedwith:a) C₁₋₄ alkoxy, b) halogen, or c) aryl or heterocycle; R⁸ isindependently selected from:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR10)--, R₁₀ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl,R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyland aryl; Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl,mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono-or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl,unsubstituted or substituted with one or two of the following:1) C₁₋₄alkyl, unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) NR⁶ R⁷, c)C_(3-C) ₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) --S(O)_(m) R⁶,or g) --C(O)NR⁶ R⁷, 2) aryl or heterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃ ; 9) --S(O)_(m) R⁶, 10) --C(O)NR⁶ R⁷, or 11)C₃ -C₆ cycloalkyl; m is 0, 1 or 2; andor a pharmaceutically acceptablesalt thereof.
 4. The compound according to claim 1 of the formula D:##STR38## wherein: R², R³ and R⁴ are independently selected from:hydrogen or C₁ -C₆ alkyl;Z is mono- or bicyclic aryl, mono- or bicyclicheteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclicheteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclicheteroarylsulfonyl, unsubstituted or substituted with one or two of thefollowing:1) C₁₋₄ alkyl, unsubstituted or substituted with:a) C₁₋₄alkoxy, b) NR⁶ R⁷, c) C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f)--S(O)_(m) R⁶, or g) --C(O)NR⁶ R⁷, 2) aryl or heterocycle, 3) halogen,4) OR⁶, 5) NR⁶ R⁷, 6) CN, 7) NO₂, 8) CF₃ ; 9) --S(O)_(m) R⁶, 10)--C(O)NR⁶ R⁷, or 11) C₃ -C₆ cycloalkyl; m is 0, 1, or 2; andor apharmaceutically acceptable salt thereof.
 5. A compound which inhibitsfarnesyl-protein transferase which is:4-1-(4-methoxybenzyl)imidazol-2-yl!-1-(2-chlorophenyl)-piperazin-2- one or4- 3-(4-methoxybenzyl)pyrid-4-yl!-1-(2-chlorophenyl)-piperazin-2-oneor apharmaceutically acceptable salt or optical isomer thereof.
 6. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 1. 7. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 3. 8. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 5. 9. A method for inhibitingfarnesyl-protein transferase which comprises administering to a mammalin need thereof a therapeutically effective amount of a composition ofclaim
 6. 10. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 7. 11. A method forinhibiting farnesyl-protein transferase which comprises administering toa mammal in need thereof a therapeutically effective amount of acomposition of claim
 8. 12. A pharmaceutical composition made bycombining the compound of claim 1 and a pharmaceutically acceptablecarrier.
 13. A process for making a pharmaceutical compositioncomprising combining a compound of claim 1 and a pharmaceuticallyacceptable carrier.